Obesity has reached epidemic proportions in industrialized countries, where it has become a leading cause of morbidity and premature mortality. Moreover, the unprecedented prevalence of this epidemic among children will likely exacerbate its future course and intensify the frequency of comorbid disorders such as diabetes, atherosclerosis and heart disease. Although lifestyle changes are the first line of treatment for obesity, when this option fails drug therapy becomes a necessity. We have recently discovered that a natural lipid compound produced by cells in the upper intestine, called oleoylethanolamide (OEA), inhibits feeding, reduces body weight and lowers serum lipids in obese rodents. OEA causes these effects by binding with nanomolar affinity to the nuclear receptor PPAR-alpha (peroxisome proliferator-activated receptor type-alpha). However, the rapid hydrolytic degradation of this natural compound shortens its biological actions and limits its potential usefulness in anti-obesity therapy. Therefore, the goal of the present proposal is to develop hydrolysis-resistant analogs of OEA with prolonged duration of action. Lead compounds identified in these Phase I studies will undergo further pharmacological, pharmacokinetic and toxicological characterization in subsequent Phase II investigations, with the ultimate objective of developing these agents into a new class of anti-obesity drugs. [unreadable] [unreadable]